Method for producing indoline compound

ABSTRACT

Provided is a salt including a compound represented by a formula (4) and a compound represented by a formula (5). A method for producing the salt includes reacting a compound represented by a formula (2) with a compound represented by a formula (3) in the presence of a quaternary onium salt and a base to form the compound represented by the formula (4); and mixing the compound represented by the formula (4) with the compound represented by the formula (5). A method for producing a compound represented by a formula (6) includes removing, from the salt including the compounds of formulae (4) and (5), a protecting group P 1 . In the following formulae, P 1  and P 2  are both protecting groups.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a Division of application Ser. No. 15/115,452, filed Jul. 29,2016, which in turn is a 371 of PCT/JP2015/052705, filed Jan. 30, 2015,which claims priority to JP 2014-207653, filed Oct. 9, 2014, JP2014-125489, filed Jun. 18, 2014, and JP 2014-021679, filed Feb. 6,2014. The disclosure of the prior applications is hereby incorporated byreference herein in its entirety.

TECHNICAL FIELD

The present invention relates to a method for producing an indolinecompound.

BACKGROUND ART

As a method for producing(−)-1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide(generic name: silodosin, which may hereinafter be referred to as“compound (1)”), there is known, for example, a method in which: acompound represented by formula (A) and a compound represented byformula (B) are reacted to obtain a compound represented by formula (C)(3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate); then the benzyl group is removed to produce a compoundrepresented by the formula (D)(7-cyano-1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole);and further the cyano group is converted into an amide group throughhydrolysis to produce the compound (1) (see Patent Literature 1, forexample).

In the meantime, three crystal forms, α-crystal, β-crystal, andγ-crystal, are known for the compound (1) (see Patent Literature 3, forexample). In particular, Patent Literature 3 discloses that theα-crystal is white and that the α-crystal is beneficial as a crystal fororal solid medicine in terms of hygroscopicity and stability.

CITATION LIST Patent Literature

Patent Literature 1: JP 5049013 B

Patent Literature 2: WO 2012/147019

Patent Literature 3: JP 4532274 B

SUMMARY OF INVENTION Technical Problem

In the method for producing the compound (1), a compound (E-1), acompound (E-2), and a compound (E-3) may be formed as impurities.

The compound (E-1) is formed when 2 moles of the compound (B) reactswith 1 mole of the compound (A) in the reaction between the compound (A)and the compound (B), followed by the leaving reaction of the benzoylgroup. The compound (D) and the compound (E-1) are similar to each otherin chemical properties and thus are difficult to separate by a commonpurification means such as a column. In addition, the compound (E-1) isconverted into the compound (E-2) when the subsequent step is performedusing a mixture of the compound (D) and the compound (E-1). The compound(E-2) is also similar to the compound (1) in chemical properties, andthey are thus difficult to separate from each other.

In relation to the above circumstances, Patent Literatures 1 and 2disclose methods in which the compound (D) is crystallized in the formof its oxalic acid salt or L-tartaric acid salt to remove the compound(E-1) and thus obtain the compound (D) of higher purity.

However, the methods described in Patent Literatures 1 and 2 cannotnecessarily give an adequate yield of the compound (1) and may fail toachieve sufficient removal of the compound (E-1). For example, in themethod using oxalic acid, the content of the compound (E-1) is 0.9% (seeExample 1 of Patent Literature 1), while in the method using L-tartaricacid, the yield of the compound (D) is low although the content of thecompound (E-1) is 0.10 to 0.16% (see Patent Literature 2).

In addition, the crystal of the oxalic acid salt of the compound (D) isdisadvantageous in terms of ease of handling since the crystal is highlyhygroscopic and readily absorbs atmospheric moisture as crystallizationwater. In the meanwhile, L-tartaric acid has been reported to inhibitintestinal absorption of phosphorus and calcium.

Furthermore, Patent Literature 2, in which crystallization of salts ofthe compound (D) with various acids is attempted, demonstrates that asolid salt is not formed when using: polycarboxylic acids such asmalonic acid, succinic acid, citric acid, and fumaric acid; esters suchas tartaric acid diester; amino acids such as L-lysine; and inorganicacids such as hydrochloric acid and sulfuric acid.

The compound (E-3) is a compound resulting from oxidation of theindoline structure of the compound (1). The compound (E-3) can be formedunder various oxidizing conditions in the course of production orpurification of the compound (1) or its crystal.

The present inventors have conducted a detailed study on the stabilityof an α-crystal of the compound (1) and, as a result, have foundproblems in that oxidation of the indoline structure is induced by heator light, causing the formation of a large amount of the compound (E-3)and also in that transformation into another crystal form is likely tooccur under a physical stimulus such as crushing.

In view of the above circumstances, the present invention aims toprovide methods for obtaining the compound (1) and its crystal of higherpurity and provide a crystal of the compound (1) of higher purity.

Solution to Problem

The present invention provides the following [1] to [15].

[1] A method for producing a compound represented by a formula (6),

the method comprising:

a step of mixing a compound represented by a formula (4)

wherein P¹ is a protecting group, and a compound represented by aformula (5)

wherein P² is a protecting group, to form a salt consisting of thecompound represented by the formula (4) and the compound represented bythe formula (5); and

a step of removing the protecting group P¹ of the salt.

[2] The method according to [1], wherein the compound represented by theformula (5) is N-acylglutamic acid.

[3] A salt comprising:

a compound represented by a formula (4)

wherein P¹ is a protecting group; and

a compound represented by a formula (5)

wherein P² is a protecting group.[4] The salt according to [3], wherein the compound represented by theformula (5) is N-acylglutamic acid.[5] A method for producing a compound represented by a formula (4)

wherein P¹ is a protecting group,

the method comprising a step of reacting a compound represented by aformula (2)

wherein P¹ is a protecting group, and a compound represented by aformula (3)

wherein X is a leaving group, in the presence of a quaternary onium saltand a base.[6] The method according to [5], wherein the quaternary onium salt is aquaternary ammonium chloride or a quaternary ammonium bromide.[7] A method for producing a γ-crystal of a compound represented by aformula (1),

the method comprising crystallizing the compound represented by theformula (1) in an alcohol solvent represented by a formula (7)[Chemical Formula 12]ROH  (7)wherein R is an alkyl group having 1 to 4 carbon atoms, or in a mixedsolvent of the alcohol solvent and an ether solvent represented by aformula (8)[Chemical Formula 13]ROR¹  (8)wherein R is an alkyl group having 1 to 4 carbon atoms and R¹ is abranched or cyclic alkyl group having 3 to 6 carbon atoms.[8] The method according to [7], wherein the alcohol solvent is at leastone solvent selected from the group consisting of methanol, ethanol,isopropyl alcohol, and t-butyl alcohol.[9] The method according to [7] or [8], wherein the ether solvent is atleast one solvent selected from the group consisting of diisopropylether, t-butyl methyl ether, and cyclopentyl methyl ether.[10] The method according to any one of [7] to [9], further comprisingadding a γ-crystal of the compound represented by the formula (1) in anamount of 1 to 50 mg relative to 1 g of the compound represented by theformula (1) to the alcohol solvent or the mixed solvent dissolving thecompound represented by the formula (1).[11] A γ-crystal of a compound represented by a formula (1), wherein thecrystal is obtained by the method according to any one of [7] to [10].

A γ-crystal of a compound represented by a formula (1), the crystaloptionally comprising as an impurity a compound represented by a formula(E-3)

wherein when a content of the compound represented by the formula (E-3)with respect to a total amount of the crystal is expressed as X % and acontent of the compound represented by the formula (E-3) as measuredafter heating of the crystal at 70° C. for 192 hours is expressed as Y%, [Y−X] (a difference between Y and X) is less than 0.040%.

[13] The crystal according to [12], wherein the crystal optionallycomprises a solvent as an impurity, and

a content of the solvent is 890 ppm or less with respect to the totalamount of the crystal.

[14] The crystal according to [12] or [13], wherein the content of thecompound represented by the formula (E-3) is 0.001 to 0.200% withrespect to the total amount of the crystal.

[15] The crystal according to any one of [12] to [14], wherein thecontent of the compound represented by the formula (E-3) is a valuecalculated on the basis of peak areas in a chromatogram as obtained bydetection using high-performance liquid chromatography at a wavelengthof 225 nm.[16] An oral medicine for treatment of dysuria, comprising the crystalaccording to any one of [11] to [15] as an active ingredient.

Advantageous Effects of Invention

With the present invention, it is possible to provide an efficientmethod for producing the compound (4) useful as an intermediate for thesynthesis of the compound (1) serving as a dysuria treatment agent.

With the present invention, it is possible to provide an efficientmethod for producing the compound (5) useful as an intermediate for thesynthesis of the compound (1) serving as a dysuria treatment agent.

With the present invention, it is possible to provide a γ-crystal withgood stability of the compound (1) and a method for producing the same.The γ-crystal with good stability of the compound (1) according to thepresent invention is a crystal that contains a small amount of remainingsolvent and that is stable to heat, light, and crushing.

DESCRIPTION OF EMBODIMENTS

The following gives a detailed description by presenting embodiments ofthe present invention. In the specification, compounds represented bythe formula (1) and the other formulae may be referred to as “compound(1)” and the like for the sake of convenience.

A “crystal” refers to a structure in which specific molecules arespatially arranged in a lattice in such a manner as to achievetranslational symmetry, and does not refer to only a structureconsisting of a single compound. The γ-crystal of the compound (1) inthe present specification may contain a solvent or the like in additionto the compound (1), as described in Patent Literature 3. In particular,“α-crystal”, “β-crystal”, and “γ-crystal” are each identified by amethod described in Patent Literature 3 and, specifically, theidentification is performed through measurement of powder X-raydiffraction.

An embodiment of the present invention is a method for producing thecompound (1). This method comprises step A, step B1, step B2, and stepC. Each of the steps will hereinafter be described in detail.

[Step A]

This step is a step of reacting a compound (2) and a compound (3) in thepresence of a quaternary onium salt and a base to form a compound (4)

wherein P¹ is a protecting group and X is a leaving group.

Compound (2)

For the formula (2), P¹ is not particularly limited as long as it is aprotecting group for a hydroxy group, and examples thereof include:alkyl groups such as a methyl group and a t-butyl group; aralkyl groupssuch as a benzyl group (Bn) and a p-methoxybenzyl group (PMB); acylgroups such as an acetyl group (Ac), a pivaloyl group (Piv), and abenzoyl group (Bz); a trimethylsilyl group (TMS); a t-butyldimethylsilylgroup (TBDMS); a triisopropylsilyl group (TIPS); and at-butyldiphenylsilyl group (TBDPS), and P¹ is preferably an aralkylgroup or an acyl group and more preferably a benzyl group or a benzoylgroup.

It should be recalled that the compound (2) can be used also in the formof a salt. In this case, the compound (2) may be used after beingconverted into a free form beforehand or may be converted into a freeform in a liquid reaction mixture.

Compound (3)

In the formula (3), X is a leaving group, and examples thereof include:halogen atoms such as fluorine, chlorine, bromine, and iodine; andhydrocarbylsulfonyloxy groups such as a methanesulfonyloxy group, anethanesulfonyloxy group, a benzenesulfonyloxy group, and ap-toluenesulfonyloxy group.

The amount of the compound (3) used is preferably 1.05 to 1.30 moles andmore preferably 1.1 to 1.25 moles relative to 1 mole of the compound(2). When the amount of the compound (3) used is within this range, itis possible to prevent only one of the materials (the compound (2) orthe compound (3)) from remaining excessively in the reaction liquidafter completion of the reaction.

Quaternary Onium Salt

Examples of the quaternary onium salt include: quaternary ammoniumchlorides such as ammonium chloride, tetramethylammonium chloride,tetraethylammonium chloride, tetrapropylammonium chloride,tetrabutylammonium chloride, tetrapentylammonium chloride,tetrahexylammonium chloride, tetraheptylammonium chloride, andtetraoctylammonium chloride; quaternary ammonium bromides such asammonium bromide, tetramethylammonium bromide, tetraethylammoniumbromide, tetrapropylammonium bromide, tetrabutylammonium bromide,tetrapentylammonium bromide, tetrahexylammonium bromide,tetraheptylammonium bromide, and tetraoctylammonium bromide; quaternaryphosphonium chlorides such as phosphonium chloride,tetramethylphosphonium chloride, tetraethylphosphonium chloride,tetrapropylphosphonium chloride, tetrabutylphosphonium chloride,tetrapentylphosphonium chloride, tetrahexylphosphonium chloride,tetraheptylphosphonium chloride, and tetraoctylphosphonium chloride; andquaternary phosphonium bromides such as phosphonium bromide,tetramethylphosphonium bromide, tetraethylphosphonium bromide,tetrapropylphosphonium bromide, tetrabutylphosphonium bromide,tetrapentylphosphonium bromide, tetrahexylphosphonium bromide,tetraheptylphosphonium bromide, and tetraoctylphosphonium bromide, andthe quaternary onium salt is preferably a quaternary ammonium chlorideor a quaternary ammonium bromide. These quaternary onium salts may beused alone or two or more thereof may be used as a mixture.

The amount of the quaternary onium salt used is preferably 0.05 to 0.30moles and more preferably 0.05 to 0.10 moles relative to 1 mole of thecompound (2). When the amount of the quaternary onium salt used iswithin this range, the quaternary onium salt can be dissolved ordispersed uniformly in the reaction liquid, providing a sufficientreaction speed.

Base

Examples of the base used in step A include: alkali metal hydroxidessuch as sodium hydroxide and potassium hydroxide; alkali metalcarbonates such as sodium carbonate and potassium carbonate; alkalimetal hydrogen carbonates such as sodium hydrogen carbonate andpotassium hydrogen carbonate; alkali metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide;and organic bases such as triethylamine and diisopropylmethylamine,among which an alkali metal carbonate is preferably used. These basesmay be used alone or two or more thereof may be used as a mixture.

The amount of the base used is preferably 1.00 to 1.50 moles and morepreferably 1.05 to 1.20 moles relative to 1 mole of the compound (2).When the amount of the base used falls within this range, it is possibleto promote the reaction and also to sufficiently trap an acid resultingfrom the reaction.

Organic Solvent

Step A may be performed in the absence of any solvent or may beperformed in the presence of an organic solvent. The organic solvent isnot particularly limited as long as it does not inhibit the reaction.Examples of the organic solvent used in step A include: alcohols such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, and t-butylalcohol; carboxylic acid esters such as ethyl acetate, isopropylacetate, and butyl acetate; nitriles such as acetonitrile andpropionitrile; amides such as N,N-dimethylformamide andN,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethylsulfoxide; and aromatic hydrocarbons such as toluene and xylene, and theorganic solvent is preferably nitriles or amides. These organic solventsmay be used alone or two or more thereof may be used as a mixture.

The amount of the organic solvent used is preferably 4 to 15 mL and morepreferably 5 to 10 mL relative to 1 g of the compound (2). When theamount of the organic solvent used is within this range, sufficientlevels of reactivity and stirrability can be achieved.

The reaction in step A is performed, for example, by a procedure inwhich the compound (2), the compound (3), the quaternary onium salt, thebase, and the organic solvent are mixed and stirred for a predeterminedperiod of time. The reaction temperature in this case is preferably 50to 100° C. and more preferably 60 to 90° C. When the reaction isperformed at a temperature within this range, it is possible to maintaina high reaction speed and, at the same time, reduce the formation of thecompound (E-1). This reaction may be performed under pressure.

The compound (4) formed in step A can be isolated or purified, forexample, by a combination of common methods such as neutralization,extraction, filtration, concentration, crystallization,recrystallization, distillation, and column chromatography. The compound(4) as formed may be used in production of the compound (1) (hydrolysisof the cyano group) without isolation or purification.

[Step B]

This step comprises: a step of reacting the compound (4) and thecompound (5) to form a salt (4′) (step B1); and a step of removing theprotecting group P¹ of the salt (4′) to form a compound (6) (step B2).

[Step B1]

This step is a step of mixing the compound (4) and the compound (5) toform the salt (4′).

wherein P¹ is a protecting group for a hydroxy group and P² is aprotecting group for an amino group.

Compound (4)

The compound (4) used in step B1 can be produced, for example, byreference to Patent Literature 1.

wherein P¹ is a protecting group for a hydroxy group.

For the formula (4), the protecting group P¹ is not particularly limitedas long as it is a protecting group for a hydroxy group. Examples of theprotecting group P¹ include: alkyl groups such as a methyl group and at-butyl group; aralkyl groups such as a benzyl group (Bn) and ap-methoxybenzyl group (PMB); acyl groups such as an acetyl group (Ac), apivaloyl group (Piv), and a benzoyl group (Bz); a trimethylsilyl group(TMS); a t-butyldimethylsilyl group (TBDMS); a triisopropylsilyl group(TIPS); and a t-butyldiphenylsilyl group (TBDPS), and the protectinggroup P¹ is preferably an aralkyl group or an acyl group and morepreferably a benzyl group or a benzoyl group.

Compound (5)

wherein P² is a protecting group for an amino group.

The compound (5) used in step B1 refers to a glutamic acid in which ahydrogen atom on nitrogen is substituted (protected) by the protectinggroup P². It is preferable for the glutamic acid to be L-glutamic acid.The protecting group P² is not limited as long as a protecting group foran amino group. Examples of the protecting group P² include: alkylgroups such as a methyl group and a t-butyl group; alkyl groups such asa benzyl group (Bn) and a p-methoxybenzyl group (PMB); acyl groups suchas an acetyl group (Ac), a pivaloyl group (Piv), and a benzoyl group(Bz); and oxycarbonyl groups such as a t-butoxycarbonyl group (Boc), abenzyloxycarbonyl group (Cbz), a 9-fluorenylmethyloxycarbonyl group(Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), and anallyloxycarbonyl group (Alloc), and the protecting group P² ispreferably an acyl group and more preferably an acetyl group.

The amount of the compound (5) used is preferably 0.5 to 1.5 moles andmore preferably 0.7 to 1.2 moles relative to 1 mole of the compound (4).When the amount of the compound (5) used is within this range,sufficient salification takes place.

For the reaction in step B1, the compound (4) and the compound (5) maybe stirred in the absence of any solvent or may be stirred in a solvent.It is preferable to stir the compound (4) and the compound (5) in asolvent in terms of improving stirrability and homogeneity. In addition,this step may be performed under heating.

The solvent used in step B1 is not particularly limited as long as itdoes not inhibit the formation of the salt (4′), and examples of thesolvent include: water; alcohols such as methanol, ethanol, isopropylalcohol, and t-butyl alcohol; carboxylic acid esters such as ethylacetate, isopropyl acetate, and butyl acetate; nitriles such asacetonitrile and propionitrile; sulfoxides such as dimethyl sulfoxideand diethyl sulfoxide; and aromatic hydrocarbons such as toluene andxylene, and the solvent is preferably water, an alcohol, a carboxylicacid ester, a nitrile, or a sulfoxide and more preferably water,isopropyl alcohol, ethyl acetate, acetonitrile, or dimethyl sulfoxide.These solvents may be used alone or two or more thereof may be used as amixture.

The amount of the solvent used is preferably 5 to 40 mL and morepreferably 15 to 25 mL relative to 1 g of the compound (4).

The reaction temperature (heating temperature) in step B1 is preferably40 to 90° C. and more preferably 50 to 70° C. When the temperature iswithin this range, the formation of the salt (4′) smoothly proceedswithout precipitation of the formed salt.

In step B1, a crystal of the salt (4′) can be precipitated by leavingthe solution containing the formed salt (4′). In this case, the solution(solution containing the salt) may be cooled or concentrated, or a poorsolvent (a solvent with a low ability to dissolve the salt (4′)) may beadded, to precipitate the crystal.

The salt (4′) obtained in step B1 has a very low content of the compound(E-1) as an impurity, and thus the salt (4′) as obtained can be used instep B2 without any problem. The salt (4′) obtained in step B1 may beused in step B2 after being subjected to isolation by filtration or thelike and optionally to washing with a solvent and drying.

[Step B2]

This step is a step of subjecting the salt (4′) to reaction underconditions which allow removal of the protecting group P¹ and therebyforming the compound (6). In step B2, removal of the protecting group P¹and desalination (removal of the compound (5)) may be performedsimultaneously or desalination may be performed after removal of theprotecting group P¹.

wherein P¹ is a protecting group for a hydroxy group and P² is aprotecting group for an amino group.

Step B2 is not particularly limited as long as it is performed underconditions which allow removal of the protecting group P¹ of the salt(4′). It is preferable to perform desalination simultaneously in stepB2. When desalination is performed simultaneously, it is preferable toperform the removal of the protecting group P¹ in a solvent in thepresence of a base.

Examples of the base used in step B2 include: alkali metal hydroxidessuch as sodium hydroxide and potassium hydroxide; alkaline-earth metalhydroxides such as calcium hydroxide; alkali metal carbonates such assodium carbonate and potassium carbonate; alkaline-earth metalcarbonates such as calcium carbonate; alkali metal hydrogen carbonatessuch as sodium hydrogen carbonate and hydrogen carbonate potassium;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium methoxide, and potassium ethoxide; and alkaline-earth metalalkoxides such as calcium methoxide, and the base is preferably analkali metal hydroxide and more preferably sodium hydroxide or potassiumhydroxide. These bases may be used alone or two or more thereof may beused as a mixture.

The amount of the base used is preferably 1 to 10 moles and morepreferably 3 to 5 moles relative to 1 mole of the salt (4′).

Examples of the solvent used in step B2 include: water; alcohols such asmethanol, ethanol, isopropyl alcohol, and t-butyl alcohol; carboxylicacid esters such as ethyl acetate, isopropyl acetate, and butyl acetate;nitriles such as acetonitrile and propionitrile; sulfoxides such asdimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons suchas toluene and xylene, among which water, alcohols, carboxylic acidesters, nitriles, or sulfoxides is preferably used, and water, isopropylalcohol, ethyl acetate, acetonitrile or dimethyl sulfoxide is morepreferably used. These solvents may be used alone or two or more thereofmay be used as a mixture.

The amount of the solvent used is preferably 1 to 10 mL and morepreferably 2 to 5 mL relative to 1 g of the salt (4′).

The reaction temperature (heating temperature) in step B2 is preferably20 to 70° C. and more preferably 45 to 55° C. When the temperature iswithin this range, the removal of the protecting group P¹ and thedesalination (formation of the compound (6)) proceed smoothly withoutprecipitation of the compound (4).

The compound (6) obtained in step B2 can be isolated or purified by acombination of common methods such as neutralization, extraction,filtration, concentration, crystallization, recrystallization,distillation, and column chromatography. The compound (6) may be used inproduction of the compound (1) without isolation or purification.

[Step C]

This step is a step of hydrolyzing the cyano group of the compound (6)to form the compound (1).

This step can be performed by a method described, for example, in PatentLiterature 1.

Next, a method for producing a γ-crystal of the compound (1), which isanother embodiment of the present invention, will be described indetail.

The crystal of the compound (1) according to the present embodiment is aγ-crystal of the compound (1) that is substantially free of the compound(E-3) and for which [Y−X] (i.e. a difference between Y and X) is lessthan 0.040% when the content of the compound (E-3) with respect to thetotal amount of the crystal is expressed as X % and the content of thecompound (E-3) as measured after heating of the crystal at 70° C. for192 hours is expressed as Y %.

In the present specification, a “γ-crystal with good stability” isidentified by the thermal stability test described later and is one forwhich [Y−X] (i.e. a difference between Y and X) is less than 0.040% whenthe content of the compound (E-3) with respect to the total amount ofthe crystal is expressed as X % and the content of the compound (E-3) asmeasured after heating of the crystal at 70° C. for 192 hours isexpressed as Y %. The crystal structure of the indoline compound isdetermined using a powder X-ray diffractometer.

The thermal stability test is a test for evaluating a change in thecontent of the compound (E-3) in the γ-crystal of the compound (1)caused when the crystal is heated at 70° C. for 192 hours. The pre-testcontent X (%) of the compound (E-3) with respect to the total amount ofthe crystal and the post-heating content Y (%) of the compound (E-3)with respect to the total amount of the crystal are measured, and theamount of change is calculated by the formula Y−X and expressed as[Y−X]. The content of the compound (E-3) may be on a mass basis or avolume basis. To measure the content of the compound (E-3) withincreased accuracy, the measurement may be performed usinghigh-performance liquid chromatography (HPLC). When the content of thecompound (E-3) is measured using HPLC, the content can be measured as avalue obtained as follows: a peak area of a peak observed in achromatogram and attributed to the compound (E-3) is divided by the sumof the peak areas of all the peaks.

The γ-crystal of the compound (1) according to the present embodimentmay contain the compound (E-3) as an impurity but is preferablysubstantially free of the compound (E-3). Here, “substantially free”means that the content of the compound (E-3) in the γ-crystal of thecompound (1) is within such a range that the pharmacological effect ofthe compound (1) is not affected. The range is, for example, from 0.001to 0.200% with respect to the total amount of the crystal.

It is preferable that the γ-crystal of the compound (1) used as aneffective ingredient of a medicine be substantially free of the compound(E-3); however, in consideration of production of the medicine, theγ-crystal of the compound (1) may contain the compound (E-3) in anamount of 0.001 to 0.200%. Even a γ-crystal of the compound (1) in whichthe content of the compound (E-3) is equal to or less than the lowerlimit is sufficiently usable.

A γ-crystal of the compound (1) for which [Y−X] (i.e. a differencebetween Y and X) determined in the thermal stability test is less than0.040% is excellent in terms of thermal stability and is expected to beeffective as a crystal for oral solid medicine.

The γ-crystal of the compound (1) according to the present embodimentmay contain a solvent (e.g., a solvent used for crystallization) as animpurity, but is preferably substantially free of any solvent. Here,“substantially free” means that the content of the solvent in theγ-crystal of the compound (1) is within such a range that thepharmacological effect of the compound (1) is not affected. When theγ-crystal contains a solvent, the residual solvent amount in theγ-crystal of the compound (1) is preferably 5000 ppm or less, morepreferably 890 ppm or less, and particularly preferably 500 ppm or less.The lower limit of the content of the solvent is, for example, a lowerdetection limit in gas chromatography and is, for example, 10 ppm. Theresidual solvent amount as defined herein refers to the amount of theresidue of the solvent used for crystallization in the resultingcrystal. The upper limit of the residual solvent amount is appropriatelyset on the basis of the standard for residual solvents which isspecified in guidelines provided by International Conference onHarmonisation of Technical Requirements for Registration ofPharmaceuticals for Human Use (ICH).

As described later, the γ-crystal of the compound (1) is superior instability to light and crushing to the α-crystal which has beenconventionally considered favorable, and is more effective as a crystalfor oral solid medicine than the α-crystal. Furthermore, in view of thereduced amount of the residual solvent, the γ-crystal of the compound(1) is expected to be effective, for example, as an active ingredient ofan oral medicine for treatment of dysuria.

(Method for Producing γ-Crystal with Good Stability)

The solvent used in the method for producing the γ-crystal is an alcoholsolvent represented by the formula (7)[Chemical Formula 24]ROH  (7)wherein R is an alkyl group having 1 to 4 carbon atoms, or a mixedsolvent of the alcohol solvent and an ether solvent represented by theformula (8)[Chemical Formula 25]ROR¹  (8)wherein R is an alkyl group having 1 to 4 carbon atoms and R¹ is abranched or cyclic alkyl group having 3 to 6 carbon atoms.

Examples of the alkyl group having 1 to 4 carbon atoms include a methylgroup, an ethyl group, a propyl group, and a butyl group. Examples ofthe branched alkyl group having 3 to 6 carbon atoms include an isopropylgroup, an isobutyl group, a sec-butyl group, and a t-butyl group, andexamples of the cyclic alkyl group having 3 to 6 carbon atoms include acyclopropyl group, a cyclobutyl group, and a cyclopentyl group.

In terms of ease of crystallization and reduction in residual solventamount, at least one solvent selected from the group consisting ofmethanol, ethanol, 2-propyl alcohol (isopropyl alcohol), 2-butyl alcohol(sec-butyl alcohol), and 2-methyl-2-propyl alcohol (t-butyl alcohol) isused as the alcohol solvent.

In terms of ease of crystallization and reduction in residual solventamount, it is preferable for the ether solvent to be at least onesolvent selected from the group consisting of diisopropyl ether, t-butylmethyl ether, and cyclopentyl methyl ether.

The compound (1) used in step C is not particularly limited, as long asit is in a solvent-soluble form so that it can be thoroughly dissolvedin the solvent defined above in crystallization. That is, the compound(1) is specifically in a crystalline state or a solid state and, when ina crystalline state, it is not required to take a particular crystalform. The compound (1) may be a hydrate or a solvate.

Specifically, the crystallization is performed, for example, by a methodin which the compound (1) is dissolved in a solvent and then theγ-crystal is precipitated by cooling.

The dissolution of the compound (1) in a solvent is accomplished bymixing the compound (1) and the solvent, and heating may be performed tothoroughly dissolve the compound (1). The heating temperature in thatcase is not particularly limited as long as it is a temperature whichallows thorough dissolution of the compound (1) in the solvent, and theheating temperature is preferably 40 to 90° C.

The amount of the solvent used to dissolve the compound (1) ispreferably 10 to 40 mL and more preferably 10 to 20 mL relative to 1 gof the compound (1). When the amount of the solvent used is within thisrange, the compound (1) can be thoroughly dissolved in the solvent, andthe γ-crystal is precipitated quickly by cooling.

After the compound (1) is dissolved in the solvent, the resultingsolution may be cooled to precipitate the γ-crystal. The coolingtemperature in that case is not particularly limited as long as it is atemperature which allows precipitation of the γ-crystal of the compound(1), and the cooling temperature is preferably 15 to 25° C.

In precipitation of the γ-crystal, it is desirable to add a separatelysynthesized γ-crystal of the compound (1) as a seed crystal in order topromote the precipitation (formation and growth) of the γ-crystal. Theγ-crystal of the compound (1) added as a seed crystal may be, forexample, one produced by the method described in Patent Literature 3.The amount of the seed crystal used is not particularly limited as longas it is an amount which allows promotion of the precipitation of theγ-crystal, and the amount of the seed crystal used is preferably 1 to 50mg and more preferably 1 to 10 mg relative to 1 g of the compound (1)used.

The precipitated γ-crystal can be collected by filtration followed bydrying under reduced pressure. The γ-crystal of the compound (1) can beused, for example, as an active ingredient of an oral medicine fortreatment of dysuria.

EXAMPLES

Next, the present invention will be specifically described withreference to Examples; however, the scope of the present invention isnot limited by the Examples.

Examples of Step A

Compound analysis was performed by the following equipment and method.

Analytical equipment: High-performance liquid chromatography(manufactured by Shimadzu Corporation)

Analytical Conditions:

Detector: Ultraviolet absorptiometer (measurement wavelength: 254 nm)

Column: Inertsil ODS-3 (GL Sciences Inc., 5 μm, 4.6 mm×15 cm)

Column temperature: 40° C.

Mobile phase and measurement method: 1.0 g of ammonium formate and waterwere mixed to a volume of 1000 mL, and then 0.53 mL of formic acid wasadded to adjust the pH of the solution to 3.7. The measurement wasperformed as the volume ratio between the solution and acetonitrile wasvaried from 3:7 to 9:1.

Flow rate: 1.0 mL/minute

Example A1 (Synthesis of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate)

In a container having an inner volume of 5 L and equipped with a refluxcondenser, a thermometer, and a stirrer, 317 g (0.62 moles) of3-{5-[(2R)-2-aminopropyl]-7-cyano-2,3-dihydro-1H-indol-1-yl}propiobenzoate.mono-(2R,3R)-tartrate, 1.8 L of ethyl acetate, and 1280 g (1.83moles) of a 20% aqueous potassium carbonate solution were mixed andstirred at room temperature for 1 hour.

After completion of the stirring, an organic phase was separated fromthe reaction liquid, and the obtained organic phase was concentratedunder reduced pressure. The concentrate, 1.8 L of acetonitrile, 69 g(0.65 moles) of sodium carbonate, 10 g (0.03 moles) oftetrabutylammonium bromide, and 233 g (0.74 moles) of2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate were mixedand subjected to reaction under stirring at 75 to 85° C. for 30 hours.

After completion of the reaction, the reaction liquid was cooled to roomtemperature and then filtered, with the result that 2.2 kg of anacetonitrile solution of3-({7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate (content: 14.2 mass %, 0.53 moles) was obtained (yield: 85%).

Comparative Example A1 (Synthesis of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate)

In Example A1, a reaction was performed in the similar manner as inExample A1, except that tetrabutylammonium bromide was not added.

As a result, the yield of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate was 77%.

Example A2 (Synthesis of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate)

In Example A2, a reaction was performed in the similar manner as inExample A1, except that the organic solvent was replaced by toluene.

As a result, the yield of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate was 82%.

Comparative Example A2 (Synthesis of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate)

In Comparative Example A2, a reaction was performed in the similarmanner as in Comparative Example A1, except that the organic solvent wasreplaced by toluene.

As a result, the yield of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate was 71%.

The above results reveal that the reaction speed between the compound(2) and the compound (3) is increased by the presence of a quaternaryammonium.

Examples of Step B Reference Example B (Synthesis of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate)

In a container having an inner volume of 5 L and equipped with a refluxcondenser, a thermometer, and a stirrer, 317 g (0.62 moles) of3-{5-[(2R)-2-aminopropyl]-7-cyano-2,3-dihydro-1H-indol-1-yl}propylbenzoate.mono-(2R,3R)-tartrate, 1.8 L of ethyl acetate, and 1280 g (1.83moles) of a 20% aqueous potassium carbonate solution were mixed andstirred at room temperature for 1 hour.

After completion of the stirring, an organic phase was separated fromthe reaction liquid, and the obtained organic phase was concentratedunder reduced pressure. The concentrate, 1.8 L of acetonitrile, 69 g(0.65 moles) of sodium carbonate, 10 g (0.03 moles) oftetrabutylammonium bromide, and 233 g (0.74 moles) of2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate were mixedand subjected to a reaction under stirring at 75 to 85° C. for 30 hours.

After completion of the reaction, the reaction liquid was cooled to roomtemperature and then filtered, with the result that 2.2 kg of anacetonitrile solution of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate (content: 14.2 mass %, 0.53 moles) was obtained (yield: 85%).

Example B1 (Synthesis of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate.mono-N-acetylglutamate)

In3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate (compound corresponding to the compound (4) wherein P¹ is abenzoyl group) used in this example, the content of the compound (E-1)was 12.3%.

In a container having an inner volume of 10 L and equipped with a refluxcondenser, a thermometer, and a stirrer, the acetonitrile solution of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate obtained in Reference Example 1 and 3.9 L of acetonitrile weremixed, and the mixed liquid was heated to 50 to 60° C.

Subsequently, 143 mL of a dimethyl sulfoxide solution of 116.7 g (0.62moles) N-acetylglutamic acid was added to the mixed liquid, to which0.12 g of(3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate.mono-N-acetylglutamate was then added as a seed crystal. Thiswas followed by stirring at 50 to 60° C. for 2 hours.

After completion of the stirring, the mixed liquid was cooled to 0° C.,and the crystal precipitated was filtered. The resulting crystal waswashed with 1.6 L of cooled acetonitrile and then dried to obtain 398 g(0.52 moles) of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate.mono-N-acetylglutamate in the form of a colorless, transparentcrystal (yield: 98%).

In this case, the content of the dialkylated compound was reduced belowthe detection limit.

It should be noted that3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate.mono-N-acetylglutamate is a novel compound characterized by thefollowing physical property values.

Melting point: 142 to 148° C.

¹H-NMR (DMSO-d₆, δ (ppm)): 0.95 (3H, d), 1.74 to 1.81 (1H, m), 1.84 (3H,s), 1.86 to 1.91 (1H, m), 2.03 to 2.10 (2H, m), 2.23 to 2.28 (2H, m),2.35 (1H, dd), 2.66 (1H, dd), 2.88 to 3.04 (5H, m), 3.57 (2H, t), 3.68(2H, t), 4.07 (2H, t), 4.14 to 4.19 (1H, m), 4.38 (2H, t), 4.66 (2H, q),6.90 to 7.10 (6H, m), 7.50 (2H, t), 7.65 (1H, t), 7.96 (1H, s), 7.99(2H, d)

Example B2 (Synthesis of1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile)

In a container having an inner volume of 10 L and equipped with a refluxcondenser, a thermometer, and a stirrer, 285 g (0.37 moles) of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate.mono-N-acetylglutamate obtained in Example B1, 370 g (1.52moles) of a 23 mass % aqueous potassium hydroxide solution, and 720 mLof methanol were mixed and subjected to a reaction under stirring at 45to 50° C. for 1 hour.

After completion of the reaction, the reaction liquid was cooled to roomtemperature, which was followed by addition of 850 mL of water and 2540mL of ethyl acetate, then thorough stirring, and then separation of anorganic layer. The obtained organic layer was washed with an aqueoussodium hydrogen carbonate solution and an aqueous ammonium chloridesolution, was then concentrated under reduced pressure and, afteraddition of 360 mL of ethanol, was concentrated under reduced pressureto obtain 175 g (0.37 moles) of1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile(yield: 99%).

Examples B2 to B4 and Comparative Examples B1 to B32 (Synthesis of3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate.mono-N-acetylglutamate)

Reactions were performed in the similar manner as in Example B1, exceptthat the type of the acid was varied from that in Example B1. Theresults are shown in Table 1.

TABLE 1 Content of compound Acid Solvent State (E-1) [%] Example B1N-acetylglutamic acid Acetonitrile/Dimethyl Crystal <0.1  sulfoxideExample B2 N-acetylglutamic acid Acetonitrile Crystal 0.1 Example B3N-acetylglutamic acid Isopropyl alcohol Crystal 1.2 Comparative Oxalicacid Isopropyl alcohol Crystal 3   Example B1 Comparative L-tartaricacid Isopropyl alcohol Oily — Example B2 Comparative D-tartaric acidIsopropyl alcohol Crystal 9.2 Example B3 ComparativeN-acetylphenylalanine Toluene Crystal 1.6 Example B4 ComparativeN-acetylphenylalanine Ethyl acetate Crystal 3.8 Example B5 ComparativeN-acetylphenylalanine Isopropyl alcohol Solution — Example B6Comparative Sulfuric acid Isopropyl alcohol Crystal 4.7 Example B7Comparative Phthalic acid Isopropyl alcohol Oily — Example B8Comparative Maleic acid Isopropyl alcohol Solution — Example B9Comparative Fumaric acid Isopropyl alcohol Oily — Example B10Comparative Malonic acid Isopropyl alcohol Solution — Example B11Comparative Succinic acid Isopropyl alcohol Solution — Example B12Comparative L-malic acid Isopropyl alcohol Oily — Example B13Comparative Hydrochloric acid Isopropyl alcohol Solution — Example B14Comparative Hydrobromic acid Isopropyl alcohol Solution — Example B15Comparative Phosphoric acid Isopropyl alcohol Oily — Example B16Comparative P-toluenesulfonic acid Isopropyl alcohol Solution — ExampleB17 Comparative Methanesulfonic acid Isopropyl alcohol Solution —Example B18 Comparative Benzenesulfonic acid Isopropyl alcohol Solution— Example B19 Comparative (−)-camphorsulfonic Isopropyl alcohol Solution— Example B20 acid Comparative (+)-camphorsulfonic Isopropyl alcoholSolution — Example B21 acid Comparative Benzoic acid Isopropyl alcoholSolution — Example B22 Comparative P-nitrobenzoic acid Isopropyl alcoholOily — Example B23 Comparative P-chlorobenzoic acid Isopropyl alcoholSolution — Example B24 Comparative P-hydroxybenzoic Isopropyl alcoholSolution — Example B25 acid Comparative N-acetylcysteine Isopropylalcohol Solution — Example B26 Comparative N-acetylglycine Isopropylalcohol Solution — Example B27 Comparative N-acetylaspartic acidIsopropyl alcohol Solution — Example B28 Comparative Ascorbic acidIsopropyl alcohol Oily — Example B29 Comparative Citric acid Isopropylalcohol Oily — Example B30 Comparative Acetic acid Isopropyl alcoholSolution — Example B31 Comparative Trifluoroacetic acid Isopropylalcohol Solution — Example 32

The above results show that, in most cases of the used acids, a saltwith3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate could not be obtained in the form of a solid crystal, while asalt of the compound and N-acetylglutamic acid could be obtained in theform of a crystal from all solvents.

It was also found that among the salts obtained in the form of acrystal, those obtained when using N-acetylglutamic acid as an acid hada very low content of the compound (E-1).

Examples of Step C

(Compound Analysis)

Compound analysis was performed in the same manner as in the aboveexamples of step A, except that the measurement wavelength and themobile phase were changed as follows.

Measurement wavelength: 225 nm

Mobile phase and measurement method: 1.0 g of ammonium formate and waterwere mixed to a volume of 1000 mL, and then 0.53 mL of formic acid wasadded to adjust the pH of the solution to 3.7. The measurement wasperformed as the volume ratio between the solution and acetonitrile wasvaried from 4:1 to 1:1.

The content of the compound (E-3) was expressed as a value calculated asfollows: a peak area of a peak observed in a chromatogram and attributedto the compound (E-3) was divided by the sum of peak areas of all peaksobserved in the chromatogram.

(Crystal Structure Analysis)

Analysis equipment: Powder X-ray diffractometer, RINT-TTR III(manufactured by Rigaku Corporation)

Example C1 (Production of γ-Crystal of Compound (1) Using IsopropylAlcohol Solvent)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 30 gof the compound (1) and 300 mL of isopropyl alcohol, which were heatedto 45° C. to thoroughly dissolve the compound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 35° C., then by addition of 3 mg of a γ-crystal of thecompound (1) as a seed crystal, then by natural cooling at roomtemperature overnight, and then by cooling to decrease the solutiontemperature to 6° C. The resulting crystal precipitated was filtered.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 23 g of a γ-crystal ofthe compound (1) in the form of a white crystal (yield: 79%).

The amount of the residual solvent in the obtained crystal was 495 ppm.

(Thermal Stability Test)

A thermal stability test was conducted on the γ-crystal obtained inExample C1.

Content (X) of compound (E-3) measured before test: 0.043%

Content (Y) of compound (E-3) measured after test: 0.044%

[Y−X] was 0.001%, i.e., the increase in the content of the compound(E-3) observed during the test was small, which means that the γ-crystalwas stable.

Comparative Example C1 (Production of γ-Crystal of Compound (1) UsingToluene Solvent)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 15 gof the compound (1) and 300 mL of toluene, which were heated to 65° C.to thoroughly dissolve the compound (1).

The dissolution was followed by repeated cycles of heating and coolingto decrease the solution temperature to 23° C., and the resultingcrystal precipitated was filtered. The filterability was good.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 15 g of a γ-crystal ofthe compound (1) in the form of a white crystal (yield: 98%).

The amount of the residual solvent in the obtained crystal was 2564 ppm.

(Thermal Stability Test)

A thermal stability test was conducted on the γ-crystal obtained inComparative Example C1.

Content (X) of compound (E-3) measured before test: 0.091%

Content (Y) of compound (E-3) measured after test: 0.133%

[Y−X] was 0.042%, i.e., the increase in the content of the compound(E-3) observed during the test was large, which means that the γ-crystalwas unstable.

Example C2 (Production of γ-Crystal of Compound (1) Using IsopropylAlcohol Solvent)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 30 gof the compound (1) and 300 mL of isopropyl alcohol, which were heatedto 45° C. to thoroughly dissolve the compound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 35° C., then by addition of 50 mg of a γ-crystal of thecompound (1) as a seed crystal, and then by repeated cycles of heatingand cooling to decrease the solution temperature to 4° C. The resultingcrystal precipitated was filtered.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 24 g of a γ-crystal ofthe compound (1) in the form of a white crystal (yield: 80%).

The amount of the residual solvent in the obtained crystal was 873 ppm.

(Thermal Stability Test)

A thermal stability test was conducted on the γ-crystal obtained inExample C2.

Content (X) of compound (E-3) measured before test: 0.076%

Content (Y) of compound (E-3) measured after test: 0.088%

[Y−X] was 0.012%, i.e., the increase in the content of the compound(E-3) observed during the test was small, which means that the γ-crystalwas stable.

Example C3 (Production of γ-Crystal of Compound (1) Using IsopropylAlcohol and t-Butyl Methyl Ether Solvents)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 30 gof the compound (1), 100 mL of isopropyl alcohol, and 200 mL of t-butylmethyl ether, which were heated to 45° C. to thoroughly dissolve thecompound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 5° C., then by addition of 20 mg of a γ-crystal of thecompound (1) as a seed crystal, and then by repeated cycles of heatingand cooling to decrease the solution temperature to 5° C. The resultingcrystal precipitated was filtered. 14-0741

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 25 g of a γ-crystal ofthe compound (1) in the form of a white crystal (yield: 82%).

In the obtained crystal, the amounts of the residual solvents, isopropylalcohol and t-butyl methyl ether, were 157 ppm and 104 ppm,respectively, and the total amount of the residual solvents was 261 ppm.

(Thermal Stability Test)

A thermal stability test was conducted on the γ-crystal obtained inExample C3.

Content (X) of compound (E-3) measured before test: 0.071%

Content (Y) of compound (E-3) measured after test: 0.097%

[Y−X] was 0.026%, i.e., the increase in the content of the compound(E-3) observed during the test was small, which means that the γ-crystalwas stable.

Example C4 (Production of γ-Crystal of Compound (1) Using IsopropylAlcohol and t-Butyl Methyl Ether Solvents)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 25 gof the compound (1), 75 mL of isopropyl alcohol, and 225 mL of t-butylmethyl ether, which were heated to 55° C. to thoroughly dissolve thecompound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 50° C., then by addition of 20 mg of a γ-crystal of thecompound (1) as a seed crystal, and then by repeated cycles of heatingand cooling to decrease the solution temperature to 5° C. The resultingcrystal precipitated was filtered.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 21 g of a γ-crystal ofthe compound (1) in the form of a white crystal (yield: 85%).

In the obtained crystal, the amounts of the residual solvents, isopropylalcohol and t-butyl methyl ether, were 16 ppm and 104 ppm, respectively,and the total amount of the residual solvents was 120 ppm.

(Thermal Stability Test)

A thermal stability test was conducted on the γ-crystal obtained inExample C4.

Content (X) of compound (E-3) measured before test: 0.067%

Content (Y) of compound (E-3) measured after test: 0.091%

[Y−X] was 0.024%, i.e., the increase in the content of the compound(E-3) observed during the test was small, which means that the γ-crystalwas stable.

Reference Example C1 (Production of Crystal of Compound (1) Using MethylIsobutyl Ketone Solvent)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 30 gof the compound (1) and 300 mL of methyl isobutyl ketone, which wereheated to 60° C. to thoroughly dissolve the compound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 50° C., then by addition of 6 mg of a γ-crystal of thecompound (1) as a seed crystal, and then by repeated cycles of heatingand cooling to decrease the solution temperature to 20° C. The resultingcrystal precipitated was filtered. The filterability was good.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 26 g of a mixedcrystal of an α-crystal and a γ-crystal of the compound (1) in the formof a white crystal (yield: 86%).

Reference Example C2 (Production of Crystal of Compound (1) UsingIsopropyl Acetate Solvent)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 15 gof the compound (1) and 300 mL of isopropyl acetate, which were heatedto 60° C. to thoroughly dissolve the compound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 50° C., then by addition of 16 mg of a γ-crystal of thecompound (1) as a seed crystal, and then by repeated cycles of heatingand cooling to decrease the solution temperature to 6° C. The resultingcrystal precipitated was filtered.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 14 g of a mixedcrystal of an α-crystal and a γ-crystal of the compound (1) in the formof a white crystal (yield: 91%).

The above results confirmed that a γ-crystal obtained by the productionmethod of the present invention has good stability to heat and has a lowcontent of the residual solvent.

Reference Example C3 (Photostability Test and Crushing Stability Test)

An α-crystal, a β-crystal, and a γ-crystal were produced, and each ofthem was subjected to a photostability test and a crushing stabilitytest under the following conditions.

(Conditions of Photostability Test)

Each crystal was left under irradiation of 4000-lux light at 25° C. anda relative humidity of 60% for 336 hours.

(Conditions of Crushing Stability Test)

Each crystal was put in a mortal and crushed with a pestle.

(Production of α-Crystal)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 10 gof the compound (1) and 130 mL of ethyl acetate, which were heated to70° C. to thoroughly dissolve the compound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 26° C., and the resulting crystal precipitated wasfiltered.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 9 g of an α-crystal ofthe compound (1) in the form of a white crystal (yield: 88%).

(Photostability Test)

The photostability test was conducted on the obtained α-crystal.

Content of compound (E-3) measured before photostability test: 0.037%

Content of compound (E-3) measured after photostability test: 0.960%

For the α-crystal, the content of the compound (E-3) was increased by0.923% as a result of the photostability test.

(Crushing Stability Test)

The crushing stability test was conducted on the obtained α-crystal.

As a result, it was confirmed that the α-crystal is transformed into aγ-crystal.

(Production of β-Crystal)

In a container having an inner volume of 2000 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 60 gof the compound (1) and 900 mL of isopropyl acetate, which were heatedto 60° C. to thoroughly dissolve the compound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 20° C., and the resulting crystal precipitated wasfiltered.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 54 g of a β-crystal ofthe compound (1) in the form of a white crystal (yield: 91%).

(Photostability Test)

The photostability test was conducted on the obtained β-crystal.

Content of compound (E-3) measured before photostability test: 0.027%

Content of compound (E-3) measured after photostability test: 0.419%

For the β-crystal, the content of the compound (E-3) was increased by0.392% as a result of the photostability test.

(Crushing Stability Test)

The crushing stability test was conducted on the obtained β-crystal.

As a result, phase transition was not observed after the crushing.

(Production of γ-Crystal)

In a container having an inner volume of 300 mL and equipped with areflux condenser, a thermometer, and a thermometer there were put 30 gof the compound (1) and 150 mL of isopropyl alcohol, which were heatedto 40° C. to thoroughly dissolve the compound (1).

The dissolution was followed by cooling to decrease the solutiontemperature to 3° C., and the resulting crystal precipitated wasfiltered.

Subsequently, the obtained crystal (filtered product) was dried byheating (45° C.) under reduced pressure to obtain 26 g of a γ-crystal ofthe compound (1) in the form of a white crystal (yield: 86%).

(Photostability Test)

The photostability test was conducted on the obtained γ-crystal.

Content of compound (E-3) measured before photostability test: 0.024%

Content of compound (E-3) measured after photostability test: 0.321%

For the γ-crystal, the content of the compound (E-3) was increased by0.297% as a result of the photostability test.

(Crushing Stability Test)

The crushing stability test was conducted on the obtained γ-crystal.

As a result, phase transition was not observed after the crushing.

The above results of the photostability test confirmed that theγ-crystal of the present embodiment has good stability to light and thatthe α-crystal is the most unstable.

The results of the crushing stability test confirmed that the γ-crystalof the present embodiment does not undergo phase transition even whensubjected to crushing and is thus considered to have good stability andthat the α-crystal is the most unstable.

The invention claimed is:
 1. A salt comprising: a compound representedby the following formula (4):

 wherein P¹ is a protecting group; and a compound represented by thefollowing formula (5):

 wherein P² is a protecting group.
 2. The salt according to claim 1,wherein the compound represented by the formula (5) is N-acylglutamicacid.
 3. A method for producing the salt according to claim 1, themethod comprising: reacting a compound represented by the followingformula (2):

 wherein P¹ is a protecting group, with a compound represented by thefollowing formula (3):

wherein X is a leaving group, in the presence of a quaternary onium saltand a base to form the compound represented by the formula (4); andmixing the compound represented by the formula (4) with the compoundrepresented by the formula (5).
 4. The method according to claim 3,wherein the quaternary onium salt is a quaternary ammonium chloride or aquaternary ammonium bromide.
 5. A method for producing a compoundrepresented by the following formula (6):

the method comprising: removing, from the salt according to claim 1, theprotecting group P¹.